When Experiments Travel: Clinical Trials and the Global Search for Human Subjects

Help, Harm and Human Subjects

A review by Sheldon Krimsky

Those of you who browse bulletin boards or ride in buses or subway cars have undoubtedly come across posters bearing messages like this: "If you are between the ages of 18 and 35 and have difficulty sleeping, you may qualify to participate in a new study that could help your condition." Such solicitations are now nearly ubiquitous. That's because the clinical trial business has grown significantly over the past several decades, largely in response to the growth of drug development and of global markets in pharmaceuticals. To get new drugs into the marketplace, companies must deliver safety and efficacy data from clinical trials to the U.S. Food and Drug Administration (FDA). It is estimated that every year about 2.3 million people take part in clinical trials held in the United States; in 2008, more than 65,000 such trials, sponsored by federal agencies and private industry, were listed in a National Institutes of Health (NIH) database for those trying to locate clinical trials.

Investment in drug development has grown steadily since the 1980s as a result of biomedical advances relating to stem cell research, pharmacogenetics, proteomics and the mapping of the human genome. Recently the drug industry has been spending the money it budgets for research and development on a new generation of cancer drugs. As Big Pharma has investigated these oncologic agents, more volunteers have been needed in clinical trials to evaluate the prospects of various compounds.

Many trials have had difficulty recruiting subjects. According to a 2006 article by Judith M. Watson and David J. Torgerson, "Increasing Recruitment to Randomized Trials" (BMC Medical Research Methodology 6:34), a survey of the corresponding authors of articles published in 2000 or 2001 reporting the results of randomized trials revealed that nearly 60 percent of the trials had either proceeded with fewer subjects than initially planned or found it necessary to extend the recruitment period.

And more recently Sarah Kliff, in an article published online in Newsweek on March 10, 2009, has reported that 80 percent of clinical trials are delayed at least a month because of low enrollment.

When people cannot be recruited for trials in the United States, the world marketplace becomes the stage for medical outsourcing. Eastern Europe, Africa, Asia and South America have helped fill the demand for human trial subjects, usually with indigent people who have little or no access to health care. According to a report from Visiongain (a company that provides business information to the pharmaceutical industry), in 2008 the global clinical trial business was worth about $50 billion and was growing at a rate of 10 percent a year.

Three recently published books address the subject of clinical trials from different vantage points. When Experiments Travel, by Adriana Petryna, is an ethnographic analysis of leaders in the new growth industry of Contract Research Organizations (CROs), which provide clinical-trial services to drug developers. Exploitation and Developing Countries, edited by Jennifer S. Hawkins and Ezekiel J. Emanuel, is a volume of essays by bioethicists focusing on issues of global equity and justice in clinical trials that enroll impoverished groups in developing nations. And Chasing Medical Miracles is journalist Alex O'Meara's memoir of his experiences jumping through hoops to gain access to a clinical trial that gave hope of a cure for his diabetes.

In When Experiments Travel, Petryna, an anthropologist at the University of Pennsylvania, explores this question: Why are so many of the clinical trials sponsored by companies in the United States being held in developing nations? To explain the phenomenon known as "offshoring of trials," Petryna analyzes information gleaned from government sources, the Web sites of nonprofit organizations, and interviews with leading scientists and entrepreneurs who have founded CROs. She learns that, as is true of many trends in globalization, government policies play a central role. "In the early 1990s," she notes, "the FDA began to actively promote the globalization of clinical trials, declaring that the search for sites and sources of data is part of its mandate."

After examining the global marketplace for human subjects, Petryna concludes that the norms of protection vary significantly among countries. The book is built primarily on her scholarly, detached presentation of qualitative interview data and an analysis of published statistics. However, she periodically expresses moral judgments such as the following: "The benefits deriving from globalized research are arguably uncertain, and its risks are unevenly distributed and its costs, unjust."

Petryna condemns First World companies and complicit governments for exploiting vulnerable, impoverished patients as experimental subjects. However, many of the complex ethical issues of transnational human trials are left unexplored in her book. Among those are whether desperate people can be both exploited and helped, and what set of humane principles should guide outsourced clinical trials. These are the subjects of the volume edited by Hawkins and Emanuel, Exploitation and Developing Countries.

The essays in this collection are organized primarily around two cases, which serve as the grist for ethical analysis. In the Havrix case, 40,000 school children in Thailand received either an inactivated hepatitis A vaccine or a hepatitis B vaccine in a randomized controlled trial sponsored by the U.S. Army in conjunction with SmithKline Beecham Biologicals and Thailand's Ministry of Public Health. In the Surfaxin case, 650 premature infants in Bolivia who had respiratory distress syndrome (RDS), for which the standard treatment was lung surfactant replacement therapy with one of four approved surfactant drugs, were subjects in a placebo-controlled trial of a new surfactant made by Discovery Labs. In addition, in the introduction to Exploitation and Developing Countries, there is a discussion of trials in sub-Saharan Africa in which women were treated with antiviral agents to reduce maternal-fetal transmission of HIV.

The essayists reflect on a series of moral dilemmas. Can there be informed voluntary consent when the clinical trials are conducted in countries in which people face extreme poverty, illness and desperation? Is it ethical to use placebo controls against a new drug in clinical trials when some form of effective therapy exists for a medical condition and is the standard of care? When is a clinical trial protocol exploitative of desperate human subjects? Should U.S. companies engaged in overseas trials be required to follow ethical and medical standards that are no less stringent than those they would be required to follow in the United States? Or should the moral acceptability of a trial be based on whether the company's actions will improve the lives of the population of the country where the trial will be conducted?

A number of the essays address the complex issue of placebos. Thomas Pogge ("Testing Our Drugs on the Poor Abroad") explores the question of whether it is "wrong to test a new medicine (Surfaxin) for some life-threatening medical condition (RDS) with a placebo-control design when there already exists an effective medicine for this condition against which the new drug could be tested." Pogge points out that if the Surfaxin trial had had an active control design, the lives of more than 280 infants might have been saved; nevertheless, with the placebo-control design, the trial saved the lives of 140 infants who probably would have died if the trial had not been conducted in Bolivia.

The book's contributors examine responses to ethical questions through the lens of a variety of ethical theories: utilitarianism (greatest good for the greatest number), deontology (respect for persons), virtue ethics (accepted standards and norms), Rawlsian justice (the most vulnerable must not be made worse off), situation ethics (contextualized to local conditions) and intuitionism (what feels fundamentally fair and just). The meaning of exploitation in the circumstances discussed remains elusive; nevertheless, the volume's artful philosophical analyses illuminate the issues. Andrew Siegel, in "Kantian Ethics, Exploitation and Multinational Clinical Trials," expresses the paradoxical dialectic:

We must also exercise caution when legislating against exploitation, for the perverse reality is that the best prospect some persons currently have for improving their lives is to submit to exploitative exchanges.

In "Exploitation and Placebo Controls," Jennifer Hawkins proffers a set of conditions that she believes are jointly sufficient to morally justify the use of placebo controls even when participants fail to receive the best care available.

The last chapter consists of a consensus statement obtained from participants at an international conference on research in developing countries. It addresses the question of whether it is unethical to recruit persons in a poor country to be clinical-trial subjects when neither they nor their country will benefit from the medical advance being investigated.

Overall, these are essays of high quality. However, the anthology is limited in one obvious respect: It has no contributions (with the exception of the consensus statement) from ethicists in those parts of the world most adversely affected by clinical-trial outsourcing.

The two books already discussed, which are soberly academic in tone, were written by scholars pursuing broad explanatory themes and universal ethical principles. Alex O'Meara's Chasing Medical Miracles, the first-person account of a clinical-trial subject, is almost breezy in comparison -- the book is a page-turner.

O'Meara, a journalist, has type I diabetes complicated by hypoglycemic unawareness that has repeatedly landed him in emergency rooms. He describes the lengths to which he goes to be included in a somatic gene therapy trial that would afford him some hope that his body would begin producing its own insulin. What makes his memoir unique and captivating is that he steeped himself in the culture of clinical trials, entering not as a naive and ill-informed subject but as a fully informed and tenacious advocate of the trial, which he hoped would liberate him from having to wear an insulin pump. His personal story is so compelling that the intervening background chapters feel like an unwelcome intrusion.

The trial involved transplanting pancreatic islet cells from matched donors into the livers of patients with diabetes. To be cleared for participation, O'Meara had to overcome a number of obstacles. To take just one example, an x-ray of his lung revealed a nodule. He volunteered to undergo surgical removal of the nodule, hoping that it would turn out to be fungal, since in that case he would still be eligible for the trial. The surgeon needed 98 titanium staples to close his lung after the surgery. "I saw the little rivets on my x-ray," O'Meara writes. "They were looking great, the surgeon said. And no, he told me, the staples wouldn't set off metal detectors at airports."

If the book has a weakness, it is that the author makes it appear that, to qualify for a trial, a candidate must be in tip-top physical shape (O'Meara was a marathon runner). His case is hardly representative of the way people actually get recruited for trials or of the type of medical screening that usually takes place to ensure that the trial candidate meets the letter of the protocol.

O'Meara's trial was fraught with risks, and things did not go smoothly for him: He experienced multiple complications and got mixed results. Thus his experience left him well qualified to write the book's useful afterword, in which he presents a set of soul-searching questions that anyone who is considering enrolling in a clinical trial would do well to consider.

Chasing Medical Miracles provides a useful counterpoint to the detached, scholarly approach of social scientists and ethicists featured in the other two books. It reminds us that people in desperation over their illnesses seek hope, and that many of them grasp that hope in a clinical trial that offers them an experimental treatment. Taken together, these three books reveal the profound complexity of the task of meeting the needs of vulnerable populations while advancing medical science for the benefit of future generations.

Sheldon Krimsky is a professor in the Department of Urban and Environmental Policy and Planning at Tufts University and an adjunct professor in the Department of Public Health and Community Medicine at Tufts University School of Medicine. He is the author of, among other books, Science in the Private Interest (Rowman and Littlefield, 2004) and is coauthor with Tania Simoncelli of Genetic Justice (forthcoming from Columbia University Press).

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